MAJOR CAUSE OF AGE-RELATED MEMORY LOSS
Study points to possible treatments and confirms distinction between memory loss due to aging and that of Alzheimer’s
From the News Desk of Jeanne Hambleton
Source Newsroom: Columbia University Medical Center
Newswise — NEW YORK, NY — A team of Columbia University Medical Center (CUMC) researchers, led by Nobel laureate Eric R. Kandel, MD, has found that deficiency of a protein called RbAp48 in the hippocampus is a significant contributor to age-related memory loss and that this form of memory loss is reversible.
The study, conducted in postmortem human brain cells and in mice, also offers the strongest causal evidence that age-related memory loss and Alzheimer’s disease are distinct conditions.
The findings were published today in the online edition of Science Translational Medicine.
“Our study provides compelling evidence that age-related memory loss is a syndrome in its own right, apart from Alzheimer’s. In addition to the implications for the study, diagnosis, and treatment of memory disorders, these results have public health consequences,” said Dr. Kandel, who is University Professor & Kavli Professor of Brain Science, co-director of Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute, director of the Kavli Institute for Brain Science, and senior investigator, Howard Hughes Medical Institute, at CUMC.
Dr. Kandel received a share of the 2000 Nobel Prize in Physiology or Medicine for his discoveries related to the molecular basis of memory.
The hippocampus, a brain region that consists of several interconnected subregions, each with a distinct neuron population, plays a vital role in memory.
Studies have shown that Alzheimer’s disease hampers memory by first acting on the entorhinal cortex (EC), a brain region that provides the major input pathways to the hippocampus.
It was initially thought that age-related memory loss is an early manifestation of Alzheimer’s, but mounting evidence suggests that it is a distinct process that affects the dentate gyrus (DG), a subregion of the hippocampus that receives direct input from the EC.
“Until now, however, no one has been able to identify specific molecular defects involved in age-related memory loss in humans,” said co-senior author Scott A. Small, MD, the Boris and Rose Katz Professor of Neurology and Director of the Alzheimer’s Research Center at CUMC.
The current study was designed to look for more direct evidence that age-related memory loss differs from Alzheimer’s disease.
The researchers began by performing microarray (gene expression) analyses of postmortem brain cells from the DG of eight people, ages 33 to 88, all of whom were free of brain disease.
The team also analyzed cells from their EC, which served as controls since that brain structure is unaffected by aging. The analyses identified 17 candidate genes that might be related to aging in the DG. The most significant changes occurred in a gene called RbAp48, whose expression declined steadily with aging across the study subjects.
To determine whether RbAp48 plays an active role in age-related memory loss, the researchers turned to mouse studies.
“The first question was whether RbAp48 is down regulated in aged mice,” said lead author Elias Pavlopoulos, PhD, associate research scientist in neuroscience at CUMC.
“And indeed, that turned out to be the case—there was a reduction of RbAp48 protein in the DG.”
When the researchers genetically inhibited RbAp48 in the brains of healthy young mice, they found the same memory loss as in aged mice, as measured by novel object recognition and water maze memory tests.
When RbAp48 inhibition was turned off, the mice’s memory returned to normal.
The researchers also did functional MRI (fMRI) studies of the mice with inhibited RbAp48 and found a selective effect in the DG, similar to that seen in fMRI studies of aged mice, monkeys, and humans.
This effect of RbAp48 inhibition on the DG was accompanied by defects in molecular mechanisms similar to those found in old mice. The fMRI profile and mechanistic defects of the mice with inhibited RbAp48 returned to normal when the inhibition was turned off.
In another experiment, the researchers used viral gene transfer and increased RbAp48 expression in the DG of aged mice.
“We were astonished that not only did this improve the mice’s performance on the memory tests, but their performance was comparable to that of young mice,” said Dr. Pavlopoulos.
“The fact that we were able to reverse age-related memory loss in mice is very encouraging,” said Dr. Kandel.
“Of course, it is possible that other changes in the DG contribute to this form of memory loss. But at the very least, it shows that this protein is a major factor, and it speaks to the fact that age-related memory loss is due to a functional change in neurons of some sort.
Unlike with Alzheimer’s, there is no significant loss of neurons.”
Finally, the study data suggest that RbAp48 protein mediates its effects, at least in part, through the PKA-CREB1-CBP pathway, which the team had found in earlier studies to be important for age-related memory loss in the mouse.
According to the researchers, RbAp48 and the PKA-CREB1-CBP pathway are valid targets for therapeutic intervention. Agents that enhance this pathway have already been shown to improve age-related hippocampal dysfunction in rodents.
“Whether these compounds will work in humans is not known,” said Dr. Small.
“But the broader point is that to develop effective interventions, you first have to find the right target. Now we have a good target, and with the mouse we have developed, we have a way to screen therapies that might be effective, be they pharmaceuticals, nutraceuticals, or physical and cognitive exercises.”
“There has been a lot of handwringing over the failures of drug trials based on findings from mouse models of Alzheimer’s,” Dr. Small said.
“But this is different. Alzheimer’s does not occur naturally in the mouse. Here, we have caused age-related memory loss in the mouse, and we have shown it to be relevant to human aging.”
The researchers have identified a protein—RbAp48—that, when increased in aged wild-type mice, improves memory back to that of young wild-type mice. In the image, yellow shows the increased RbAp48 in the dentate gyrus.
Image credit: Elias Pavlopoulos, PhD/Columbia University Medical Center
The paper is titled, “A Molecular Mechanism for Age-Related Memory Loss: The Histone Binding Protein RbAp48.”
The other contributors are Sidonie Jones, Stylianos Kosmidis, Maggie Close, Carla Kim, and Olga Kovalerchik, all at CUMC.
The authors declare no financial or other conflicts of interests.
The study was supported by grants from the Howard Hughes Medical Institute, the James S. McDonnell Foundation, the Broitman Foundation, the Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., the McKnight Brain Research Foundation, and the National Institute on Aging (AG034618).
The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University Medical Center is a multidisciplinary group that has forged links between researchers and clinicians to uncover the causes of Alzheimer’s, Parkinson’s, and other age-related brain diseases and to discover ways to prevent and cure these diseases.
It has partnered with the Gertrude H. Sergievsky Center at Columbia University Medical Center, which was established by an endowment in 1977 to focus on diseases of the nervous system, and with the Departments of Pathology & Cell Biology and of Neurology to allow the seamless integration of genetic analysis, molecular and cellular studies, and clinical investigation to explore all phases of diseases of the nervous system.
The Department of Neuroscience at Columbia University Medical Center
CUMC’s Department of Neuroscience, whose faculty includes two Nobel laureates, focuses on fundamental aspects of neural circuit development, organization, and function, using cutting-edge biophysical, cellular imaging, and molecular genetic approaches.
Its faculty have backgrounds in a range of fields, including molecular and cell biology, systems neuroscience, theoretical neuroscience, and biophysics.
Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast.
STORING MEMORIES OF RECENT EVENTS
From the News Desk of Jeanne Hambleton
Source: National Institute of Health
Citation – U.S. Department of Health & Human Services
Memories of recent events may be held by a small number of neurons distributed across the brain’s hippocampus, a new study suggests. Understanding how the brain stores memories will yield insights into memory problems that come with normal aging and dementia.
The hippocampus plays a critical role in memory. Much prior memory research has focused on semantic memory—remembering facts, such as famous people and landmarks.
Exposure to a particular face or place becomes linked to a small number of neurons in the hippocampus; these neurons then fire when the memory is recalled. But how the brain forms episodic memories—the memories of events—is not well understood.
Researchers have proposed at least 3 different ways that the brain might encode episodic memories.
In a localist scheme, an individual neuron would code for one memory, and each memory would be linked to the activity of one neuron.
In a fully distributed scheme, each memory would be coded by a pattern of activity across many neurons.
In a sparse distributed scheme, each memory would be coded by the activity of a small proportion of neurons, and each neuron would contribute to a few memories.
A research team led by Dr. Peter N. Steinmetz of the Barrow Neurological Institute in Phoenix, Arizona, and Drs. John T. Wixted and Larry R. Squire, of the University of California, San Diego, investigated how episodic memories were encoded. Their study was funded in part by NIH’s National Institute of Mental Health (NIMH) and National Institute on Deafness and Other Communications Disorders (NIDCD). It appeared online on June 16, 2014, in Proceedings of the National Academy of Sciences.
The scientists were able to explore the mechanisms of memory at the single-neuron level by studying the brains of 9 patients with severe epilepsy who were being treated at the Barrow Neurological Institute.
The patients had depth electrodes implanted into several brain structures, including the hippocampus. These tiny electrodes are used to pinpoint seizure-causing brain regions for possible surgical removal. They can also be used to gather information about how individual brain cells process memories.
The patients were first asked to study 32 target words. They then took a word recognition test with 32 targets from the study list and 32 “foils” that weren’t on the list.
They rated the words on an 8-point scale, from 1 when they were sure it was new to 8 when they were sure it was old. Each of the 64 items on the test was presented only once to ensure that the targets, but not the foils, were represented by an episodic memory.
If the items had been presented many times, the results might simply highlight neurons that respond to long-established semantic memories, rather than to words recently studied.
Together, the patients completed a total of 18 tests. The scientists found that a small percentage of recorded neurons (less than 2%) responded to any one target. Likewise, a small percentage of targets (about 3%) evoked a strong response in any one neuron. This pattern suggests that the human hippocampus uses a sparse distributed code to store episodic memories.
“To really understand how the brain represents memory, we must understand how memory is represented by the fundamental computational units of the brain—single neurons—and their networks,” Steinmetz says.
“Knowing the mechanism of memory storage and retrieval is a critical step in understanding how to better treat the dementing illnesses affecting our growing elderly population.”
—by Harrison Wein, Ph.D.
Reference: Sparse and distributed coding of episodic memory in neurons of the human hippocampus. Proc Natl Acad Sci U S A. 2014 Jun 16. doi: 10.1073/pnas.1408365111. [Epub ahead of print].
Funding: NIH’s National Institute of Mental Health (NIMH) and National Institute on Deafness and Other Communications Disorders (NIDCD); Department of Veterans Affairs, the Barrow Neurological Foundation, and the University of California, San Diego Kavli Institute for Brain and Mind.
FOOD FOR THOUGHT
I received an email with the following interesting thoughts. It does make you value what you have. I just hope by sharing this message I am not in breech of any unknown copyright. This is without payment and in the interest of education.
This is something we should all remember.
A 92-year-old, petite, well-poised and proud man, who is fully dressed each morning by eight o’clock, with his hair fashionably combed and shaved perfectly, even though he is legally blind, moved to a nursing home today.
His wife of 70 years recently passed away, making the move necessary. After many hours of waiting patiently in the lobby of the nursing home, he smiled sweetly when told his room was ready.
As he manoeuvred his walker to the elevator, the nurse provided a visual description of his tiny room, including the eyelet sheets that had been hung on his window.
‘I love it,’ he stated with the enthusiasm of an eight-year-old having just been presented with a new puppy.
‘Mr. Jones, you have not seen the room; just wait..’
‘That does not have anything to do with it,’ he replied.
‘Happiness is something you decide on ahead of time.
‘Whether I like my room or not does not depend on how the furniture is arranged .. it is how I arrange my mind. I already decided to love it.
‘It is a decision I make every morning when I wake up. I have a choice;
‘I can spend the day in bed recounting the difficulty I have with the parts of my body that no longer work, or get out of bed and be thankful for the ones that do.
‘Each day is a gift, and as long as my eyes open, I will focus on the new day and all the happy memories I have stored away.. Just for this time in my life..
‘Old age is like a bank account. You withdraw from what you have put in.
‘So, my advice to you would be to deposit a lot of happiness in the bank account of memories!
‘Thank you for your part in filling my Memory Bank.
‘I am still depositing.
‘Remember the five simple rules to be happy:
1. Free your heart from hatred.
2. Free your mind from worries.
3. Live simply.
4. Give more.
5. Expect less.
‘Please share these thoughts. Have a nice day, unless you already have other plans.’
A great philosphy I think. Wonderful if you have the will power to do this and live happily. Certainly this is food for thought.
If everyone considered other folks and understood how valuable life really is, we might not have all these recent pointless deaths and aircrash said to be through thoughtless actions. Every day I am more convinced that quite often men make war and women make love.
Talk again tomorrow. Jeanne